This invention relates to a process for the selective partial oxidation of alkylheteroaromatic compounds, particularly nitrogen-containing heteroaromatics, for the production of heteroaromatic carboxylic acids, such as nicotinic acid.
Pyridinecarboxylic acids derived from methylpyridines are important intermediates in the pharmaceutical industry. In particular, 3-pyridinecarboxylic acid or nicotinic acid, which is used as a precursor of vitamin B3, has been manufactured on a large scale. Two basic methods are employed for the synthesis of pyridinecarboxylic acids. One method is based on the hydrolysis of pyridinecarboxamides derived from pyridinecarbonitriles, and the other is the oxidation of alkylpyridines by air, nitric acid, selenium dioxide etc. The ammoxidation of methylpyridines forms pyridinecarbonitriles, which are subsequently hydrolyzed to pyridinecarboxylic acids through pyridinecarboxamides. 3-Pyridinecarboxylic acid has been commercially manufactured by nitric acid oxidation of 5-ethyl-2-methylpyridine.
The selective oxidation of alkyl heteroaromatic compounds to the carboxylic acid is known to be significantly more difficult than the corresponding carbocyclic compounds. The residence time required for the oxidation of alkyl heteroaromatic compounds to the carboxylic acid is significantly higher than for the equivalent carbocyclic alkyl aromatic compounds. For example, JP-07233150 (Nissan Chemical International) disclosed a process for the production of nicotinic acid from 3-methyl pyridine by oxidation in acetic acid using a Cobalt Manganese Cerium Bromide catalyst for which the required reaction time was 3 hours. Similar studies for p-xylene to terephthalic acid oxidation give a required residence time of 40 minutes or less (U.S. Pat. No. 3,354,202).
Conventional methods require long residence times, and produce significant amounts of undesirable by-products. By-products include partially-oxidised intermediates of the target carboxylic acid, such as aldehyde intermediates. For instance, the oxidation of 3-methylpyridine (3-Mpy) to produce 3-pyridinecarboxylic acid (3-PyA), can result in significant levels of 3-pyridinecarboxaldehyde (3-PyAl). In addition, decarboxylation of the product can give rise to the unsubstituted heteroaromatic compound itself, which is pyridine in the oxidation of 3-methylpyridine.
JP-2002-226404 (Daicel Chemical Industries Ltd) disclosed a process for the production of nicotinic acid from 3-methyl pyridine in acetic acid using N-hydroxyphthalimide as a promoter for oxidation in acetic acid. However, the process requires long residence times and is economically unfeasible since it produces substantial quantities of phthalimide and phthalate impurities from the added promoter.
The commercial gas phase process for the oxidation of 3-methylpyridine to nicotinic acid described in DE-19822788 (Lonza AG) suffers from several disadvantages. Since the reaction is exothermic, carrying it out in the gas phase gives rise to heat transfer limitations that reduce the efficiency with which energy can be removed from the reaction. Also since the reaction is carried out over a fixed bed heterogeneous catalyst, reaction can only occur at the surface of the catalyst rather than throughout the fluid medium.
There remains a need to provide improved processes for the production of heteroaromatic carboxylic acids, particularly one in which reaction times and by-product formation are reduced.
It would also be desirable to avoid the use of substantial amounts of organic solvent, such as acetic acid, which is relatively costly and, due to environmental restrictions, may require recovery and recycling. A further problem with the use of acetic acid is that it is flammable when mixed with air or oxygen under certain conditions. A further problem with the use of organic solvents is that the oxidant may have low solubility therein. For instance, where dioxygen is used as the oxidant, the dioxygen is present predominantly as discrete bubbles in the reaction medium with only a small proportion of the dioxygen dissolving in the solvent. To the extent that the reaction between the precursor and the dioxygen results from the dioxygen diffusing from the bubbles into the bulk liquid, the reaction rate is limited by the low solubility of dioxygen in the solvent.
It has now been found that heteroaromatic carboxylic acids can be synthesised by oxidation of a precursor in supercritical water.
Holliday R. L. et al (J. Supercritical Fluids 12, 1998, 255-260) describe a batch process for the synthesis of, inter alia, aromatic carboxylic acids from alkyl aromatics in a reaction medium of sub-critical water using molecular oxygen as the oxidant. The dielectric constant of water decreases dramatically from a room temperature value of around 80 C2/Nm2 to a value of 5 C2/Nm2 as it approaches its critical point (374° C. and 220.9 bara), allowing it to solubilise organic molecules. As a consequence, water then behaves like an organic solvent to the extent that hydrocarbons, e.g. toluene, are completely miscible with the water under supercritical conditions or near supercritical conditions. Terephthalic acid, for instance, is virtually insoluble in water below about 200° C. Dioxygen is also highly soluble in sub- and super-critical water.
International patent application WO 02/06201 discloses a continuous process for the production of aromatic carboxylic acids, such as terephthalic acid or isophthalic acid, comprising oxidising one or more precursors of the carboxylic acid in an aqueous solvent under supercritical conditions or near supercritical conditions close to the supercritical point.
It is an object of this invention to provide an alternative and improved process for the production of a heteroaromatic carboxylic acid in high yield and selectivity, and with reduced reaction times, and wherein the need to use an organic material as solvent is eliminated. It is a further object of this invention to provide an alternative and improved process for the production of a heteroaromatic carboxylic acid wherein substantially all the reactants and product are maintained in a common phase during reaction.